What is the recommended first‑line regimen for an adult with confirmed Helicobacter pylori infection who has no drug allergies and no recent macrolide or quinolone use?

Treatment of Helicobacter pylori Infection

Bismuth quadruple therapy for 14 days is the definitive first-line treatment for adults with confirmed H. pylori infection who have no drug allergies and no recent macrolide or quinolone use, achieving 80–90% eradication rates regardless of local clarithromycin resistance. 1, 2

First-Line Regimen: Bismuth Quadruple Therapy

The recommended 14-day regimen consists of:

• High-dose proton pump inhibitor (PPI) twice daily – esomeprazole or rabeprazole 40 mg is strongly preferred over other PPIs, as it increases cure rates by 8–12% 1, 2
• Bismuth subsalicylate 262 mg (two tablets) four times daily 1, 2
• Metronidazole 500 mg three to four times daily (total 1.5–2 g daily) 1, 2
• Tetracycline 500 mg four times daily 1, 2

Administration details:

• Take PPI 30 minutes before meals on an empty stomach, without concomitant antacids 1
• Take bismuth 30 minutes before meals and at bedtime 1
• Take metronidazole 30 minutes after meals 1

Why Bismuth Quadruple Therapy Is First-Line

Clarithromycin resistance now exceeds 15–20% in most of North America and Europe, making traditional triple therapy achieve only ~70% eradication rates (dropping to ~20% with resistant strains). 1, 2 Bismuth quadruple therapy is unaffected by clarithromycin resistance and maintains 80–90% efficacy even against dual clarithromycin-metronidazole-resistant strains because bismuth's synergistic effect overcomes metronidazole resistance in vitro. 1, 2

No bacterial resistance to bismuth has been described, and tetracycline resistance remains rare (<5%). 1

Treatment Duration Is Mandatory

The 14-day duration is non-negotiable; extending therapy from 7 to 14 days improves eradication success by approximately 5%. 1, 2, 3, 4 All major guidelines (American Gastroenterological Association, Toronto Consensus, Maastricht V/Florence) mandate 14 days. 1, 4

Alternative First-Line Regimens (Restricted Use Only)

Clarithromycin-based triple therapy (PPI + clarithromycin 500 mg BID + amoxicillin 1000 mg BID for 14 days) may be considered only in regions with documented clarithromycin resistance <15% and no prior macrolide exposure. 1, 2, 3 However, because most regions now exceed this threshold, this option is rarely appropriate. 1, 2

Concomitant non-bismuth quadruple therapy (PPI BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID + metronidazole 500 mg BID for 14 days) is an alternative only when bismuth is unavailable and local clarithromycin resistance is <15%. 1, 2

Second-Line Treatment After First-Line Failure

If bismuth quadruple therapy fails, use levofloxacin triple therapy for 14 days (high-dose PPI BID + amoxicillin 1000 mg BID + levofloxacin 500 mg once daily), provided the patient has no prior fluoroquinolone exposure. 1, 2, 3, 4

If clarithromycin-based triple therapy fails (in the rare scenario it was used first-line), switch to bismuth quadruple therapy for 14 days. 1, 2

Never repeat clarithromycin or levofloxacin if they were in the failed regimen; resistance develops rapidly after exposure, dropping eradication rates from ~90% to ~20%. 1, 2

Third-Line (Rescue) Therapy

After two documented eradication failures with confirmed patient adherence, obtain antibiotic susceptibility testing to guide further treatment. 1, 2, 3, 4

Empiric third-line options include:

• Rifabutin triple therapy (rifabutin 150 mg BID + amoxicillin 1000 mg BID + high-dose PPI BID for 14 days) 1, 2
• High-dose dual therapy (amoxicillin 2–3 g daily in 3–4 divided doses + high-dose PPI BID for 14 days) 1, 2

Confirmation of Eradication

Test for eradication success at least 4 weeks after completing therapy using a urea breath test or validated monoclonal stool antigen test. 1, 2, 3 Discontinue PPI at least 2 weeks before testing to avoid false-negative results. 1, 2, 3

Never use serology for test-of-cure, as antibodies persist long after successful eradication. 1, 2

Critical Pitfalls to Avoid

• Never use once-daily PPI dosing; it is a major cause of treatment failure. 1, 2
• Avoid pantoprazole 40 mg; its acid-suppression potency is equivalent to only ~9 mg omeprazole, yielding inferior outcomes. 1, 2
• Do not shorten therapy below 14 days; this reduces eradication by ~5%. 1, 2, 3, 4
• Do not assume low clarithromycin resistance without local surveillance data; most regions now have high resistance rates. 1, 2
• Never repeat antibiotics that failed previously, especially clarithromycin and levofloxacin. 1, 2
• Metronidazole can be reused with bismuth due to synergistic effects; amoxicillin and tetracycline can be reused because resistance remains rare. 1, 2

Patient Factors Affecting Success

Smoking roughly doubles the odds of eradication failure (OR ~1.95); advise cessation during therapy. 1 Elevated BMI/obesity may lower gastric mucosal drug concentrations, potentially reducing efficacy. 1 Poor compliance is a leading cause of failure; provide clear written instructions and counsel on expected side effects (diarrhea occurs in 21–41% of patients during the first week). 1